DESCRIPTION

NeoTect® (Kit for the Preparation of Technetium Tc 99m Depreotide Injection)
is intended for use in the preparation of Technetium Tc 99m Depreotide, a diagnostic
radiopharmaceutical to be used by intravenous injection. Each vial contains
a sterile, non-pyrogenic lyophilized mixture of 47 µg of Depreotide,
75 mg of sodium glucoheptonate dihydrate, 50 µg of stannous chloride
dihydrate (with a minimum stannous tin content of 20 µg), 100 µg
edetate disodium dihydrate, 10 mg of sodium iodide, and sufficient sodium hydroxide
or hydrochloric acid for adjustment to pH 7.4 prior to lyophilization. The lyophilized
powder is sealed under a nitrogen atmosphere with a rubber closure. The product
contains no antimicrobial preservative.

Physical Charateristics

Technetium Tc 99m decays by isomeric transition with a physical half- life of 6.02 hours. The photon that is useful for imaging studies is listed in Table 1.

Table 1. Principal radiation emission data for Technetium
Tc 99m

Radiation

Mean Percent per Disintegration

Mean Energy (keV)

Gamma-2

89.07

140.5

External radiation

The specific gamma-ray constant for Technetium Tc 99m is 5.4 microcoulombs/kg·MBq·hour (0.78 R/mCi·hour) at 1 cm. The first half- value thickness of lead for Technetium Tc 99m is 0.17 mm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from the interposition of various thicknesses of lead is shown in Table 2. For example, the use of a 0.25 cm thickness of lead will decrease the external radiation exposure by a factor of 1,000.

Table 2. Radiation attenuation by lead shielding.

Lead Shield Thickness (cm)

Coefficient of Attenuation

0.017

0.5

0.08

10-1

0.16

10-2

0.25

10-3

0.33

10-4

To correct for physical decay of this radionuclide, the fractio ns that remain at selected intervals relative to the time of calibration are shown in Table 3.

DOSAGE AND ADMINISTRATION

For imaging, NeoTect® (technetium tc 99m depreotide injection) is administered as a peripheral intravenous injection at a single dose of 15 to 20 mCi containing approximately 47µg of Technetium Tc 99m radiolabeled Depreotide peptide.

Patients should drink at least an 8 oz. glass of water before drug administration.

The contents of Kit for the Preparation of Technetium Tc 99m Depreotide Injection
are intended only for use in the preparation of Technetium Tc 99m Depreotide
Injection and are not to be administered directly to the patient. Only one patient
dose should be drawn from each reconstituted vial. (See Instructions for
the Preparation Section).

The potential need for dose adjustment has not been studied in patients with renal insufficiency, or in pediatric or geriatric patients, or in patients on therapeutic somatostatin analogues.

Imaging

Planar and SPECT images of the chest should be obtained between 2-4 hours after NeoTect® (technetium tc 99m depreotide injection) administration. SPECT images of the chest are required for optimal image interpretation.

Radiation Dostmetry

Based on human data, the absorbed radiation dose to an average human adult (70 kg) from an intravenous injection of the agent are listed in Table 9. The values are listed in descending order as rad/mCi and mGy/MBq and assume urinary bladder emptying at 4.8 hours.

INSTRUCTIONS FOR THE PREPARATION OF TECHNETIUM Tc 99m DEPREOTIDE INJECTION

Use aseptic technique throughout. The user should wear waterproof gloves and use shielding at all times when handling the reconstituted vial or syringes containing the radioactive agent.

The patient doses should be measured using a suitably calibrated radioactivity dose meter immediately prior to administratio n to the patient.

Prepare a lead shielded rolling-boil water bath or equivalent heating block.

Allow the kit vial to warm to room temperature (20 to 25°C) and place
it in a suitable shielding container and sanitize the rubber septum with a
sanitizing alcohol swab.

Using a shielded syringe, inject the required activity of up to 50 mCi (1.8
GBq) of Sodium Pertechnetate Tc 99m Injection (diluted as appropriate with
0.9% Sodium Chloride Injection, U.S.P., to a total volume of one milliliter)
into the shielded vial. (See Cautionary Notes 1 and 2). Before removing
the syringe from the vial, withdraw a volume of gas from above the solution
equal to the volume of pertechnetate added in order to normalize the pressure
inside the vial. Mix for 10 seconds in order to ensure complete dissolution
of the powder.

Immediately transfer the reaction vial to the lead shielded boiling water
bath or heating block, maintaining the vial in the upright condition. Incubate
for 10 minutes in this condition. Allow the vial to cool to body temperature
(about 10 ± 2 minutes). Insert a sterile venting needle with 0.22 µm
filter into the vial and draw 1 mL of filtered air into the headspace by removing
1 mL of air with a sterile needle and syringe. .

Assay the total radioactivity, complete the user radiation label, and attach
it to the vial.

Parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration, whenever solution and container
permit: visually inspect the reconstituted solution at a safe distance through
leaded glass. Do not use if the solution is not clear or if it contains foreign
particulate matter.

Store the reconstituted injection at room temperature (20 - 25°C)
and use within six hours of preparation.

Cautionary Notes

Add 15 to 50 mCi of Sodium Pertechnetate Tc 99m Injection in a total volume
of 1 mL to obtain a single patient dose of 15 to 20 mCi from the entire reconstituted
vial.

Safety and effectiveness of Technetium Tc 99m Depreotide Injection were
established using investigational material shown to have a radiochemical purity
of at least 90% prior to administration to patients in clinical studies.

The contents of the Kit for the Preparation of Technetium Tc 99m Depreotide
Injection vial are not radioactive; however, after the addition of Sodium
Pertechnetate Tc 99m Injection, adequate shielding of the final preparation
must be maintained.

The labeling reaction involved in the preparation of Technetium Tc 99m
Depreotide Injection depends upon maintaining tin in the divalent (reduced)
state. Any oxidant present in the Sodium Pertechnetate Tc 99m Injection might
adversely affect the quality of the preparation. Sodium Pertechnetate Tc 99m
Injection containing oxidants ought not to be used for the preparation of
the labeled product.

0.9% Sodium Chloride Injection, U.S.P., must be used as the diluent. Do
not use bacteriostatic sodium chloride as a diluent for pertechnetate because
it might adversely affect the radiochemical purity and, hence, the biological
distribution of the tracer.

The contents of Kit for the Preparation of Technetium Tc 99m Depreotide
Injection are sterile and non-pyrogenic.

Quality Control

An assay of the radiochemical purity of the prepared injection can be performed using the following chromatographic procedures.

Equipment and Materials

Two Gelman ITLC-SG strips (2 cm x 10 cm)

Two glass developing jars and covers

Saturated sodium chloride solution (SAS) See #7a

1:1 (v/v) Methanol: 1M Ammonium Acetate (MAM) See #7b

One 1-mL syringe and 21- gauge (or smaller gauge) needle

Suitable counting equipment

Preparation of reagents

Saturated sodium chloride solution (SAS):SAS may be prepared by adding about five grams of sodium chloride
to the bottom of one chromatography chamber; add approximately 10 milliliters
of distilled water to the solid sodium chloride and shake periodically
during 10 to 15 minutes. Solid sodium chloride should remain at the bottom
of the jar; if there is no residue, add more solid sodium chloride and
shake again for 10 to 15 minutes. Continue until a solid residue remains.
(The Saturated Sodium Chloride Solution can be reused. Add more distilled
water or sodium chloride as needed for subsequent use, always maintaining
some undissolved sodium chloride at the bottom of the chamber.)

1:1 Methanol: 1M Ammonium Acetate (MAM):1M Ammonium Acetate: Add 3.9 ± 0.1 grams of solid ammonium
acetate to a 50 mL volumetric flask. Add approximately 15 mL of distilled
water to the flask, stopper, and swirl to dissolve the solid. Add distilled
water up to the 50 mL mark, mix thoroughly. The ammonium acetate solution
can be used for up to one month. Label the solution with a one month expiration
date.
1:1 Methanol: 1M Ammonium Acetate (MAM): Carefully mix one part methanol
with one part 1M Ammonium Acetate. The MAM should be prepared fresh daily.

Method

Pour the MAM and SAS into separate glass developing jars to a depth of approximately
0.5 cm. Cover the jars and allow to equilibrate with the solvent vapors.

Mark two Gelman ITLC-SG strips with a light pencil at 1 cm from the bottoms
of each.

Spot one drop (approximately 5 to 10 microliters) of Technetium Tc 99m Depreotide
Injection at the origin of each strip using the hypodermic needle. Do not
allow the spots to dry. CAUTION: Do not allow the needle to touch the strip.

Place the developing jars behind a lead shield.

Place one ITLC-SG strip in the MAM developing solvent. Place the second
ITLC-SG strip in the SAS developing solvent. Place the strips upright in the
respective developing solvent such that the spot is above the solvent line
and the top of the strip leans against the side of the jar. CAUTION: Do not
allow the sides of the strip to contact the side of the jar. Cap the developing
jars.

Allow the solvent front to move to the top of the strip.

Remove the strip from the jar and allow the strip to dry behind a lead shield.

Cut the strips as described below:
ITLC-SG MAM: cut the strip at Rf 0.4 (40% of the distance from the origin
to the solvent front)
ITLC-SG SAS: cut the strip at Rf 0.75 (75% of the distance from the origin
to the solvent front)

Count each strip section in a dose calibrator and interpret the results
as follows (refer to figure below):

A value of at least 90% should be obtained in a satisfactory preparation.

If the radiochemical purity of the Technetium Tc 99m Depreotide Injection
is not ≥ 90% do not administer to patients.

HOW SUPPLIED

Each kit is comprised of one vial containing a sterile, non-pyrogenic, freeze-dried mixture of Depreotide, stannous chloride dihydrate, sodium glucoheptonate dihydrate, sodium iodide and edetate disodium dihydrate. Kits are available as individual vials or as packs of five.

This reagent kit is approved for distribution to persons licensed by the U.S. Nuclear Regulatory Commission to use byproduct material identified in §35.200, or under an equivalent license of an Agreement State.

SIDE EFFECTS

Adverse events were evaluated in clinical studies of 647 adults who received 15.0 to 20.0 mCi Technetium Tc 99m labeled to approximately 47µg of depreotide. Of these adults, 58% were men and 42% women. The mean age was 59.0 years (18-86 years).

Deaths did not occur during the clinical study period. After Technetium Tc 99m Depreotide Injection, serious adverse events were not reported.

WARNINGS

None.

PRECAUTIONS

General

Therapy with somatostatin analogues can produce severe hypoglycemia in patients with insulinomas. Since Depreotide binds to somatostatin receptors caution should be exercised when administering this drug to patients with insulinomas.

NeoTect® (technetium tc 99m depreotide injection) , as other small peptides, may induce hypersensitivity reactions or anaphylactic reactions. Adequate treatment provisions, including epinephrine, should be available for immediate use. In preliminary studies of 18 subjects, NeoTect® (technetium tc 99m depreotide injection) did not produce increases in IgG or IgM production 3 weeks following injection. Other immune parameters such as eosinophils, other immunoglobulins, complement, lymphokines or cytokines were not studied.

NeoTect® (technetium tc 99m depreotide injection) contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides.

Technetium Tc 99m Depreotide Injection, like other radioactive drugs, must be handled with care and appropriate safety measure should be used to minimize radiation exposure to clinical personnel. Care should also be taken to minimize radiation exposure to the patient consistent with proper patient management.

Radiopharmaceuticals should be used by or under the control of physicians who
are qualified by specific training and experience in the safe use and handling
of radionuclides, and whose experience and training have been approved by the
appropriate governmental agency authorized to license the use of radionuclides.

Urinary excretion of radioactivity occurs primarily during the first 4 hours
following injection. Studies have not been done to determine the amount of radioactivity
that might be eliminated in the feces. (SeeCLINICAL
PHARMACOLOGY Section). Special precautions should be taken with incontinent
patients to minimize the risk of radioactive contamination of clothing, bed
linen, and the patient's environment.

Information For Patients

To minimize radiation absorbed dose to the bladder, adequate hydration should
be encouraged to permit frequent voiding during the first few hours after injection
of NeoTect® (technetium tc 99m depreotide injection) . This may be achieved by having patients drink at least an 8
oz. glass of water prior to drug administration. To help protect themselves
and others in their environment, patients should take the following precautions
for 12 hours after injection: whenever possible a toilet should be used and
should be flushed several times after each use and patients should wash their
hands thoroughly after each voiding or fecal elimination. If blood, urine or
feces soil the clothing, the clothing should be washed separately. Please refer
to the PATIENT INFORMATION section.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been conducted to evaluate carcinogenic potential or effects on fertility.

The results of the following genotoxicity studies with decayed Technetium Tc
99m Depreotide Injection or with depreotide were negative: Salmonella/Escherichia
coli reverse mutation assay,in vitro mouse lymphoma assay with and without
metabolic activation, and in vivo mouse micronucleus assay.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with decayed Technetium Tc 99m Depreotide Injection. It is not known whether Technetium Tc 99m Depreotide Injection can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Technetium Tc 99m Depreotide Injection should be given to a pregnant woman only if clearly needed. Studies in pregnant women have not been conducted.

Nursing Mothers

Studies have not been conducted with depreotide to determine its excretion in human milk.

Technetium Tc 99m Pertechnetate is excreted in human milk. It is not known whether Technetium Tc 99m Depreotide Injection is excreted in human milk. Caution should be exercised when Technetium Tc 99m Depreotide Injection is administered to a nursing woman. Wherever possible, infant formula should be substituted for breast milk until the technetium has been eliminated.

Pediatric Use

Safety and effectiveness of Depreotide in pediatric patients below the age of 16 years have not been established.

OVERDOSE

CONTRAINDICATIONS

CLINICAL PHARMACOLOGY

General

Technetium Tc 99m Depreotide Injection is a diagnostic radiopharmaceutical
based upon a synthetic peptide with high affinity binding to somatostatin receptors
(SSTR) in normal and abnormal tissues. (See Pharmacodynamics section for
details).

Pharmacokinetics

Technetium Tc 99m radioactivity pharmacokinetic parameters were evaluated after a single intravenous administration of Depreotide containing 15-20 mCi of Technetium Tc 99m and 47 µg of Depreotide in normal subjects and in patients with selected disorders. The pharmacokinetic values were estimated from data corrected for radioactivity decay. The total radioactivity in the blood exhibited three-exponential phases with the pharmacokinetic parameters shown in Table 4.

(a) Only radioactivity was measured. Data expressed
as mean value ± SD (n) where "n" is the number of subjects
or patients. (b) Only two lung cancer patients were studied; the calculated
values for both patients are presented.

The pharmacokinetics of Depreotide peptide without the Technetium Tc 99m have not been studied.

Protein Binding

In vivoplasma protein binding of total radioactivity (5-min plasma
sample) was determined by the centrifuge assisted ultrafiltration method. Mean
protein binding of Depreotide total radioactivity ranged from 11-21% (Table
5).

Metabolism

The metabolism and disposition of Depreotide peptide without the Technetium Tc 99m have not been studied in humans. Preliminary data from the elimination of radioactivity show that in patients and healthy volunteers at four hours after a single intravenous dose of depreotide (containing 15-20 mCi of Technetium Tc 99m and 47µg of depreotide), 71-84% of the Technetium Tc 99m in blood and 61-64% of the Technetium Tc 99m in urine are bound to depreotide. The fate of the remaining percentages has not been evaluated.

Elimination

In healthy subjects, 12% of the radioactivity is eliminated by renal clearance, the majority of which occurs by 4 hours. The elimination of the remaining 88% radioactivity has not been studied.

Special Populations

The pharmacokinetics of the Technetium Tc 99m Depreotide Injection have not been determined in geriatric, pediatric, renally impaired and hepatically impaired patients.

Gender Effect: In a study of 17 subjects (10 men and 7 women)
as shown in Table 6, women appeared to have less total clearance of radioactivity.

Drug - Drug Interactions

Formal in vivo and in vitro drug-drug interaction studies have
not been conducted.

Pharmacodynamics

In animal models and in vitro human cell lines, depreotide peptide without
the Technetium Tc 99m was shown to bind to somatostatin receptors (SSTR) that
predominantly are subtype 2, 3 and 5. SSTR 3 is a vasoactive intestinal peptide
(VIP) receptor site. The possibility of VIP stimulating activity has not been
studied.

Results of glucose tolerance tests in 9 healthy volunteers were normal after administration of depreotide peptide without the Technetium Tc 99m.

Clinical Studies

A total of 270 patients with known cancer or a high suspicion of cancer of the lung was studied in two multi-center, open administration, blind image interpretation clinical studies of Technetium Tc 99m Depreotide Injection. Of these patients, there were 168 (62%) men and 102 (38%) women with a mean age of 65 years (range: 29 to 86 years). Patients with known active pulmonary infections were excluded.

Eligible patients had either a known diagnosis of or were highly suspect for
cancer, had a lung lesion on computed tomography (CT) scan or chest x-ray, and
were scheduled for biopsy of the lesion. All patients had scintigraphic imaging
with NeoTect® (technetium tc 99m depreotide injection) at a dose of 444 to 1221 MBq (12 to 33 mCi); and 18-47µg of
peptide. The NeoTect® (technetium tc 99m depreotide injection) images were scored as positive for malignancy if there
was any uptake in the right or left lung, mediastinum or hilar region that was
not characteristic of general radiopharmaceutical regional uptake. The NeoTect® (technetium tc 99m depreotide injection)
images were scored negative if abnormal localization was not found. The criteria
for the interpretation of malignancy by CT were similarly based upon abnormal
visualization.

The NeoTect® (technetium tc 99m depreotide injection) and CT scans were interpreted blindly by three nuclear medicine physicians and three radiologists, respectively. The majority score for the presence or absence of malignancy was used in the statistical analysis. The location and score of NeoTect® (technetium tc 99m depreotide injection) and CT scan results were compared with the biopsy results of the presenting lesion identified at study enrollment. The results were analyzed for sensitivity, specificity, and accuracy (percentage of correct diagnoses). These results are presented in table 7.

(a) As percentage [confidence intervals](b) Total of 226 patients were evaluated. Sixteen patients in
Study A and 28 patients in study B were not evaluated primarily because
of missing biopsies.

The prevalence of malignancy in the evaluated 226 patients was high (75% in study A; 88% in study B). In these 226 patients, the lesions that were biopsy positive for malignancy had histopathology results consistent with squamous cell (34%), adenocarcinoma (32%), other non-small cell (21%), small cell (6%), and other malignant cell types (7%).

In these two studies of patients who were suspect for malignancy, two different
retrospective analyses were performed to explore the potential diagnostic use
of combined NeoTect® (technetium tc 99m depreotide injection) and CT blinded- image interpretations. One retrospective
analysis of a subset of 127 patients with a solitary pulmonary nodule implies
the combined interpretation improved specificity. In the other retrospective
analysis of all 226 patients who had a CT scan, the finding of a positive CT
and a positive NeoTect® (technetium tc 99m depreotide injection) image suggests an improved positive predictive value.
The clinical relevance of other combinations of image results (e.g., CT and
NeoTect® (technetium tc 99m depreotide injection) both negative, CT negative and NeoTect® (technetium tc 99m depreotide injection) scan positive; or CT
positive and NeoTect® (technetium tc 99m depreotide injection) negative) has not been determined. In all patients
or in those with a solitary pulmonary nodule, the clinical benefit of combined
interpretations has not been studied prospectively.

The clinical benefit of NeoTect® (technetium tc 99m depreotide injection) in other populations of patients (e.g., those who do not have a mass on CT and chest x-ray, and a high clinical suspicion for cancer) has not been studied. The clinical benefit of NeoTect® (technetium tc 99m depreotide injection) as a population-based screening tool has not been studied. NeoTect (technetium tc 99m depreotide injection) ® is not an alternative to CT or biopsy.

PATIENT INFORMATION

What is NeoTect (technetium tc 99m depreotide injection) used for? NeoTect (technetium tc 99m depreotide injection) is a radioactive imaging test used
to evaluate certain lung lesions in patients who test positive for lung lesions
using other imaging tests (e.g., CT or MRI) and have been diagnosed with cancer
or have a strong likelihood of cancer. NeoTect (technetium tc 99m depreotide injection) identifies certain cells that
may be associated with lung cancer and sometimes with other conditions.

If there is a history of drug reactions or allergies, emergency equipment and health care professionals trained to recognize and treat severe allergic reactions should be available when NeoTect (technetium tc 99m depreotide injection) is given.

The contents of NeoTect (technetium tc 99m depreotide injection) Kit are mixed with a radioactive solution by a health
care practitioner. NeoTect (technetium tc 99m depreotide injection) is a radioactive drug and must be handled with
care. Appropriate safety measures should be taken to minimize exposure to
clinical personnel and to the patient. NeoTect (technetium tc 99m depreotide injection) should be given only by doctors
who are licensed to use radioactive drugs.

If you have diabetes or have been diagnosed with tumors in the cells that
secrete insulin, tell your doctor. When you are given NeoTect (technetium tc 99m depreotide injection) , tell your doctor
if you experience symptoms of very low blood sugar.

To decrease the radiation absorbed by the bladder, you should drink at least
an 8 oz. glass of water before NeoTect (technetium tc 99m depreotide injection) injection to ensure frequent urination
during the first few hours after the test. The radioactive drug generally
is eliminated over about 24 hours, with the majority occurring during the
first 4 hours.

If you are unable to control your urination completely, your doctor may
insert a bladder catheter (tube) to minimize the risk of radioactive contamination
of your clothing and bed linen.

To protect yourself and others, you need to take the following precautions
for 12 hours after your dose of NeoTect (technetium tc 99m depreotide injection) :

If blood, urine, or feces gets onto clothing or linens, the clothing
or linens should be washed separately

What should I tell my doctor or health care provider?

Tell your health care provider if you are trying to become pregnant, are already pregnant, or are breast-feeding. If you are breast-feeding, it is recommended that you switch to infant formula while NeoTect (technetium tc 99m depreotide injection) is given and until the radioactive drug is eliminated from your body.

What are some possible side effects of NeoTect (technetium tc 99m depreotide injection) ? (This is NOT
a complete list of side effects reported with NeoTect (technetium tc 99m depreotide injection) . Your health care provider
can discuss with you a more complete list of side effects.)

NeoTect (technetium tc 99m depreotide injection) is generally well tolerated. Your health care provider can discuss with you a more complete list of possible side effects.